LEC39: Mendelian Inheritance Flashcards
what may changes in DNA sequence cause?
may be benign
can affect any aspect of txn/tln process
what is SNV?
single nucleotide variant
type of genetic variation
what is SNP?
single nucleotide polymorphism
benign change
what is a mutation?
pathogenic change
must be proven as pathogenic; any change is not necessarily a mutation
what is a VUS?
variant of unknown significance
change without clinical data to support whether it is benign or pathogenic
what is the rate of nucleotide variation in humans?
where do they usually occur?
50-80 de novo variants per generation
usually in intronic sequences, but sometimes not and in that case, could cause change cross-generationally
what information determines pathogenicity of a variant?
1) clinical data/phenotype
2) family info
3) type of variant
4) functional studies
5) databases/prediction models
does a DNA test necessarily make a diagnosis?
no. a variant may look pathogenic on molecular level, but patient may not have any phenotype, so isn’t pathogenic for the patient
change in txn factor binding site result?
causes loss of transactivation or inappropriate expression of a gene
result of mutation in conserved intron splice donor/acceptor site?
misspliced transcript
result of changes deep in intronic sequence?
can be benign
or
can cause splicing effects - retained intron, skipped exon, alternative splice site usage
what does mutation of ESE (exonic splice enhancer) cause?
missplicing
what does changes in sequence in coding region of transcript cause?
changes in amino acid identity:
missense mutations
nonsense mutations - premature STOP codon
insertion/deletion - alternations of reading frame
what does insertion/delition that is a multiple of 3 cause?
in-frame changes that result in gain or loss of short runs of amino acids
otherwise intact protein
what is B-globin thalassemia caused by?
decreased amount of transcript
what is gamma-globin persistence of fetal hemoglobin caused by?
increased amount of transcript
what variant effects result from a misspliced transcript?
1) retained intron
2) skipped exon
3) alternative splice junction
4) unstable transcript
what can cause variants due to transcription changes?
promoter/enhancer mutation
keeps RNA Pol Complex from binding to promoter/enhancer region
what does a promoter/enhancer mutation cause?
keeps RNA Pol Complex from binding to promoter/enhancer region
causes variants due to transcription changes
what is a microsatellite? what causes it? what does it cause?
di- and trinucleotide repeats of short tandem sequences
5-6 ntd in length
causes a kink in DNA
disruption of transcription, translation, protein function
**major cause of disease in humans **
what are the characteristics of a somatic variant?
1) mutation occurred after fertilization
2) not in all cells of the body
3) can be tissue or organ-specific
4) not passed down to offspring
what are the characteristics of a germline variant?
1) mutation occurred before fertilization
2) generally in every cell of body AND in oocytes or spermatocytes
3) passed on to next generation
for a somatic variant, when would more versus less cells be impacted?
if variants occurs closer to fertilizaiton = more cells impacted
later in development = less cells impacted
what is this?
family tree of recessive inheritance
how does recessive inheritance happen?
in enzymes/proteins that perform a function that doesn’t require 2 working copies of gene for normal cellular function
how could you test loss of function of recessively inherited protein?
test protein function
look at enzyme activity
via an enzyme assay; if what you’re studying is cleaved by an enzyme, light is emitted; those who are affected have low enzyme activity, less light, for example
when does loss of function usually occur? from what?
mutations in recessively inherited genes
from gene deletion, missense mutations affecting imp a.as, nonsense mutations, promoter/enhancer mutations
for disease to manifest in a recessively inherited gene, what must occur?
1 mutation in each chromosomal copy
what is homozygous recessive?
for recessive genes, when have 2 copies of the same recessive gene mutation
need this in order to see effect of a recessive gene
what is consanguineous homozygous mutation?
when parents of an affected individual are related, = consanguineous
same mutation thus presents